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GI Week 3 > Lecture 23: Pathogenesis of Colorectal Cancer and Strategies for Prevention > Flashcards

Lecture 23: Pathogenesis of Colorectal Cancer and Strategies for Prevention Flashcards

1
Q

What is the basis for understanding the development and management of CRC?

A

Adenoma-Carcinoma Sequence

Normal colonic mucosa  adenoma  carcinoma

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2
Q

What stem cell populations are in the colon/small intestine crypts?

A

2 different stem cell populations

  1. +4 markers
  2. CBC (columnar basal cell) markers
    • leads to absorptive enterocytes, goblet cells, paneth cells, entero-endocrine cells, and tuft cells
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3
Q

What is the significance of stem cell populations at the colon/small intestine?

A

There is an exquisite proliferation and differentiation gradient at the crypt
2 stem cell populations that adapts to injury at these sites
If this adaptational situation goes awry, you get polyps and cancer

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4
Q

What is an ACF (aberrant crypt focus)?

A

A hyperproliferative crypt

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5
Q

What is a polyp?

A

An excessive growth that occurs over time (years)

Hyperproliferative state that leads to excessive state

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6
Q

What is the definition of adenomatous polyp?

A

Low grade dysplasia

Can be sessile or pedunculated

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7
Q

What triggers the hyperproliferative state?

A

Mutation or loss of APC in the wnt pathway

Chromosome 5p

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8
Q

How do you progress from early to intermediate adenoma?

A

Mutation of the KRAS gene

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9
Q

How do you progress from intermediate adenoma to late adenoma to carcinoma?

A

Loss of DCC

Then loss of p53

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10
Q

What does APC stand for? Significance?

A

Adenomatous polyposis coli
A tumor suppressor gene
Discovered as gene mutated in FAP (familial adenomatous polyp)
First gene inactivated in 80% of sporadic colon adenomas and carcinomas

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11
Q

What is the normal function of APC?

A

APC protein sequesters beta-catenin by recruiting other proteins
APC DEGRADES B-catenin
Fucks up B-catenin function

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12
Q

What happens if Wnt ligand binds to Wnt receptor?

A

It disengages B-catenin from APC complex
B-catenin then leads to upregulation of c-myc and cyclin D1
So B-catenin = GROWTH

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13
Q

What happens when you have aberrant APC?

A

Proliferation increased and upregulated

Apoptosis decreased

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14
Q

How do APC mutations come about?

A

Two hit hypothesis
1 germline mutation
1 sporadic hit

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15
Q

What is the other 20% of sporadic CRC due to aside form APC mutation?

A

Microsatellite instability
Associated with abnormal expression of any one of at least four genes (MSH2, MSH6, MLH1 and PMS2)
Loss of mismatch repair genes = microsatellite instability = sporadic CRC

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16
Q

What is microsatellite instability?

A

When you have two nucleotides instead of one that gets inserted into a mismatch repair
This leads to a daughter chromosome that is one chromosome longer and thus abnormal

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17
Q

What is MMR?

A

Mismatch repair

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18
Q

What are the key characteristics of microsatellite instability?

A
  1. mismatch repair deficiency results in microsatellite instability
  2. Loss of activity can occur with germline mutations or by an epigenetic mechanism with gene silencing by hypermethylation of promoter region (MLH1)
  3. TGFBRII and other genes have polyA sequences that are at risk for mutation
  4. MMR genes don’t cause cancer but allow mutations in regulatory genes leading to cancer
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19
Q

What is the association between COX-2 and CRC?

A

Increased expression of COX-2 in colon cancers
Generates prostaglandins
Inhibition of cox-2 in animal models and in humans results in inhibition of tumor cell growth

20
Q

What are the risk factors for colorectal cancer?

A
  1. Aging
  2. Personal history of CRC or adenomas
  3. High fat, low-fiber diet
  4. IBD
  5. Family history of CRC
  6. Inherited colon cancer syndromes
21
Q

What are the INHERITED CRC syndromes?

A
  1. FAP
    a. Gardner’s Syndrome
    b. Attenuated FAP (AAPC or AFAP)
    c. Turcot’s Syndrome
  2. HNPCC/Lynch Syndrome
    a. Muir-Torre Syndrome
    b. Turcot’s Syndrome
22
Q

What are the hallmark features of FAP?

A

100 of polyps 5-7 cm in length
Average age of onset is 16
Cancer in mid 40s
What is the chance of cancer for untreated polyposis?
Leads to 100% risk of cancer
Risk of extracolonic tumors like upper GI (duodenal), desmoid, osteoma, thyroid, brain, skin (ie Gardner’s Syndrome)

23
Q

What is Gardner’s Syndrome?

A

A variant of FAP
Features of FAP:
i. desmoid tumors (tumors that arise from fibroblasts)
ii. Osteomas
iii. Supernumerary teeth
iv. Soft tissue skin tumors
v. Congenital hypertrophy of retinal pigment epithelium

24
Q

What are the genetics of FAP?

A

Auosomal dominant
Caused by APC mutation
30% have de novo germline mutations
Two hit hypothesis = one inherited APC allele is mutated
-second hit = sporadic during life
-loss of heterozygosity
De novo germline mutations occur in 30% of FAP cases
Some FAP features correlate with specific APC gene regions!!! (slide 41)

25
Q

What are the key characteristics of Lynch Syndrome or HNPCC (hereditary nonpolyposis colon cancer)?

A

Most common inherited CRC syndrome
Accounts for 1% to 5% of CRC cases
Autosomal dominance and penetrance of 80%
Genes belong to DNA MMR family (MLH1, MSH2, MSH6 and PMS2)

26
Q

What does MLH1, MSH2, MSH6 and PMS2 mutations suggest?

A

Lynch syndrome

27
Q

What are the clinical features of Lynch syndrome?

A

Early but variable CRC age
Tumor site is in PROXIMAL colon
Extracolonic cancers = endometrium, ovary, stomach, urinary tract, etc.

28
Q

What are the modalities available for CRC?

A

Amsterdam criteria for Lynch

Modified Bethesda guidelines for CRC

29
Q

What are the testing goals for CRC?

A
  1. Detection of colon cancer

2. Prevention of CRC

30
Q

What is screening?

A

Search for neoplasia in asymptomatic population with no prior neoplasia

31
Q

What is surveillance?

A

Evaluation of patients with prior colorectal adenomas or cancer or with UC

32
Q

What is Diagnosis?

A

Evaluation of symptomatic patients and patients with positive screening tests

33
Q

What are the screening methods for CRC?

A 
Accepted methods
	i. Fecal occult blood testing (FOBT)
	ii. Fecal immunochemical testing (FIT)
	iii. Flexible sigmoidoscopy
	iv. Colonoscopy
	v. barium enema
Evolving methods
	i. Virtual or CT colonoscopy
	ii. stool DNA testing
	iii. Peripheral blood DNA, RNA protein based assays
	iv. circulating tumor cells
34
Q

What is DCBE?

A

Double contrast barium enema

35
Q

What is the CRC screening guidelines?

A

Greater or equal to 50 or if you are at increased risk (genetic/familial)

36
Q

What are the key characteristics of Lynch Syndrome or HNPCC (hereditary nonpolyposis colon cancer)?

A

Most common inherited CRC syndrome
Accounts for 1% to 5% of CRC cases
Autosomal dominance and penetrance of 80%
Genes belong to DNA MMR family (MLH1, MSH2, MSH6 and PMS2)

37
Q

What does MLH1, MSH2, MSH6 and PMS2 mutations suggest?

A

Lynch syndrome

38
Q

What are the clinical features of Lynch syndrome?

A

Early but variable CRC age
Tumor site is in PROXIMAL colon
Extracolonic cancers = endometrium, ovary, stomach, urinary tract, etc.

39
Q

What are the modalities available for CRC?

A

Amsterdam criteria for Lynch

Modified Bethesda guidelines for CRC

40
Q

What are the testing goals for CRC?

A
  1. Detection of colon cancer

2. Prevention of CRC

41
Q

What is screening?

A

Search for neoplasia in asymptomatic population with no prior neoplasia

42
Q

What is surveillance?

A

Evaluation of patients with prior colorectal adenomas or cancer or with UC

43
Q

What is Diagnosis?

A

Evaluation of symptomatic patients and patients with positive screening tests

44
Q

What are the screening methods for CRC?

A 
Accepted methods
	i. Fecal occult blood testing (FOBT)
	ii. Fecal immunochemical testing (FIT)
	iii. Flexible sigmoidoscopy
	iv. Colonoscopy
	v. barium enema
Evolving methods
	i. Virtual or CT colonoscopy
	ii. stool DNA testing
	iii. Peripheral blood DNA, RNA protein based assays
	iv. circulating tumor cells
45
Q

What is DCBE?

A

Double contrast barium enema

46
Q

What is the CRC screening guidelines?

A

Greater or equal to 50 or if you are at increased risk (genetic/familial)

GI Week 3 (11 decks)

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